Naringenin is a Potential Anabolic Treatment for Bone Loss by Modulating Osteogenesis, Osteoclastogenesis, and Macrophage Polarization

Abstract

Bone undergoes constant remodeling of formation by osteoblasts and resorption by osteoclasts. In particular, macrophages have been reported to play an essential role in the regulation of bone homeostasis and regeneration. Naringenin, the predominant flavanone in citrus fruits, is reported to exert anti-inflammatory, anti-osteoclastic, and osteogenic effects. However, whether naringenin could modulate the crosstalk between macrophages and osteoblasts/osteoclasts remains to be investigated. In this study, we confirmed that naringenin enhanced osteogenesis and inhibited osteoclastogenesis directly. Naringenin promoted M2 transition and the secretion of osteogenic cytokines including IL-4, IL-10, BMP2, and TGF-β, while suppressing LPS-induced M1 polarization and the production of proinflammatory factors such as TNF-α and IL-1β. In addition, the coculture of primary bone mesenchymal stem cells (BMSCs)/bone marrow monocytes (BMMs) with macrophages showed that the naringenin-treated medium significantly enhanced osteogenic differentiation and impeded osteoclastic differentiation in both inflammatory and non-inflammatory environment. Moreover, in vivo experiments demonstrated that naringenin remarkably reversed LPS-induced bone loss and assisted the healing of calvarial defect. Taken together, naringenin serves as a potential anabolic treatment for pathological bone loss.

Naringenin facilitates M2 macrophage polarization after myocardial ischemia–reperfusion by promoting nuclear translocation of transcription factor EB and inhibiting the NLRP3 inflammasome pathway

“…The same results were observed in the in vitro experiments. In line with our findings, NAR can stimulate M2 transition and the production of IL‐4 and IL‐10 and suppress M1 polarization of macrophages and the release of TNF‐α and IL‐1β 48 . Moreover, NAR can accelerate M1 to M2 macrophage polarization shifts in atopic dermatitis 49 .…”

“…45 The long-term existence of M1 macrophages can lead to IA expansion in AMI, while M2 phenotypic polarization of macrophages improves infarct healing. 46 48 Moreover, NAR can accelerate M1 to M2 macrophage polarization shifts in atopic dermatitis. 49 NAR, as a naturally dominant flavone, has the ability to protect against LPS-induced lethality and prevent inflammationinduced organ damage.…”

Small extracellular vesicles derived from hypoxic preconditioned dental pulp stem cells ameliorate inflammatory osteolysis by modulating macrophage polarization and osteoclastogenesis

“…LPS and RANKL can activate NF-κB signaling by binding with TLR4 or RANK on monocytes/macrophages, respectively, leading to the transcription of large numbers of proinflammatory and osteoclast-related genes, thus inducing M1 macrophage polarization or bone-resorbing osteoclast formation [ 32 , 40 , 69 ]. Inhibiting NF-κB therefore has been considered an effective approach to inhibit proinflammatory cytokine production in macrophages, as well as osteoclast formation and bone resorptive activity [ 70 , 71 ]. In our study, Hypo-sEV suppressed the expression of NF-κB1/p105, a key functional subunit of NF-κB, to induce M2 macrophage polarization and inhibit osteoclastogenesis.…”

Research Progress of Macrophages in Bone Regeneration

“…Increasing the cell viability of macrophages, diferentiating M0 and M1 macrophages into M2 phenotype, and enhancing osteogenesis and mineralization Mokarram and Bellamkonda [113] Naringenin Promoting the transformation of macrophage M2 and signifcantly inhibiting M1 polarization, which balances bone formation and resorption by regulating macrophage polarization and cytokine secretion Zhou et al [114] Trehalose Enhancing the expression of M2 macrophage markers (Arg-1 and IL-10) and reducing the polarization of M1 macrophages by decreasing the expression of IL-6 can promote the delayed healing of bone in rats by downregulating proinfammatory mediators and enhancing M2 polarization Xu et al [115] Harmine Stimulating the macrophages from M1 phenotype to M2 phenotype, thereby increasing anti-infammatory and bone-related cytokine levels Wang et al [116] Frugoside Inhibiting M1 polarization of macrophages, thereby reducing the secretion of IL-6 and TNF-α, thereby delaying cartilage and extracellular matrix degradation and chondrocyte hypertrophy elucidate the function of macrophages in bone growth, diferent cell synthesis can be studied in vitro in the models of human bone regeneration. For instance, macrophages could be cocultured with stem cells which are mixed in calcium phosphate scafolds to promote bone growth.…”